Surviving sepsis guidelines 2012 pdf

The Surviving Sepsis Campaign recently developed and published an updated version in of the international guidelines for the assessment and. OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in The Surviving Sepsis Campaign recently developed and published an updated version in of the international guidelines for the.

The Surviving Sepsis Campaign Guidelines Committee Members of the SSC Guidelines .. key committee members was held to finalize the draft doc-. Guidelines for Management of Severe Sepsis and Septic Shock: , condensed from Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign. Objective: To provide an update to the “Surviving Sepsis Cam- Members of the SSC Guidelines Committee and Pediatric Sub- group are listed in tions appear in the printed text and are provided in the HTML and PDF ver- sions of.

Recommendations were classified into three groups: Factors Determining Strong vs. The consensus panel judged use of CVP and Sv o 2 targets to be recommended physiologic targets for resuscitation. However, during your initial assessment, you note temperature, Beneficial effects were found mostly in trials using parenteral rather than enteral glutamine. This trial reported a

Current evidence suggests dopamine should only be used in select patients with a low risk of dysrhythmias or with bradycardia.

If Mr. L's BP doesn't improve on norepinephrine, or if he requires additional BP support, the guidelines recommend vasopressin as an alternative, or added therapy. L shows signs of low cardiac output despite adequate fluid resuscitation and MAP, the guidelines recommend the addition of dobutamine as first-choice inotrope to improve cardiac output and tissue perfusion.

L is started on norepinephrine administered through his CVC. His nurse carefully titrates the infusion with the goal to maintain his MAP at 65 mm Hg or more. The attending physician inserts a radial artery catheter to continuously monitor the patient's BP.

V hydrocortisone isn't recommended if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability; I. V hydrocortisone is suggested only if fluid resuscitation and vasopressor therapy are insufficient.

L is in septic shock, he likely has developed relative adrenal insufficiency an inadequate stress response. In addition, the guidelines suggest administering hydrocortisone in a continuous infusion instead of intermittent bolus doses. Following the new guidelines, Mr. L's attending physician orders a continuous infusion of hydrocortisone over a hour period. L begins to have difficulty breathing and his nurse determines that he's agitated and confused.

The nurse auscultates bibasilar crackles. Arterial blood gases are drawn and reveal he's acidotic and hypoxic. His nurse suspects he's developing ARDS. In ARDS, diffuse, inflammatory lung injury leads to increased pulmonary vascular permeability. As a result, fluid leaks from the capillaries into the alveoli, which interferes with gas exchange.

To reduce the work of breathing and improve oxygenation, Mr. L is endotracheally intubated and placed on mechanical ventilation. PEEP is used to help prevent end-expiratory alveolar collapse and optimize gas exchange. To keep him comfortable, Mr. L is maintained on continuous I. Daily sedation interruptions and awakenings help decrease the amount of time Mr.

L is mechanically ventilated. The new guidelines offer additional support for mechanically ventilated patients with sepsis. Implementation of the ventilator bundle to prevent the development of VAP includes the following components: In addition, routine oral care with chlorhexidine is recommended to reduce the risk of VAP. Maintaining tight glycemic control is important and has been shown to decrease mortality in surgical patients. Because of his hyperglycemia, Mr.

L is started on a continuous insulin infusion and his glucose levels are closely monitored. Use of recombinant human-activated protein C rhAPC. The guidelines no longer support the use of rhAPC due to recent studies that have found it ineffective in less severely ill patients with severe sepsis.

One of the most significant changes in the guidelines is the removal of drotrecogin alfa activated Xigris , an rhAPC indicated for adult patients with severe sepsis and acute organ dysfunction. A review of the current evidence failed to support a benefit from administration of this medication. Substantial controversy regarding its benefit, safety, and cost led to the removal of this drug from the market.

Other supportive therapies for severe sepsis not recommended by the guidelines include the use of I. After several days of intensive medical and nursing care, Mr. L's clinical status begins to improve.

His lactate is 1. His urine output is adequate and his BP remains stable as his nurse weans him off the norepinephrine. He's extubated and on his way to recovery. L's story has a positive outcome due to an early diagnosis and treatment by the rapid response team. The ICU nurses supported and managed Mr. L's condition using evidence-based sepsis guidelines that have been shown to reduce mortality in patients with severe sepsis and septic shock.

L's physicians and nurses were aware of the most current Surviving Sepsis Campaign guidelines, he received the best possible care for his life-threatening condition. Sepsis is a complex condition that progresses rapidly as the infectious organism releases endotoxins into the bloodstream.

In reaction to these endotoxins, the body initiates an exaggerated immune response that causes significant vasodilatation, resulting in hypotension and decreased tissue perfusion. If left untreated, sepsis will progress to severe sepsis or septic shock, leading to multiple organ failure. Sepsis is defined as the presence of documented or suspected infection in addition to some of the following systemic manifestations of infection.

Severe sepsis is sepsis-induced tissue hypoperfusion or organ dysfunction any of the following believed to be a result of the infection Adapted and updated from: Sepsis and the systemic inflammatory response syndrome: Definitions, epidemiology, and prognosis.

In the updated guidelines, the previous management bundle was dropped and the resuscitation bundle was broken into two parts. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: Crit Care Med.

Procalcitonin PCT is a precursor of the hormone calcitonin, which along with parathyroid hormone helps regulate the body's calcium and phosphate balance. In healthy individuals, PCT is produced by specialized cells in the thyroid, lung, and intestine.

PCT isn't normally detected in the blood; however, in response to systemic inflammation, serum levels will rise significantly if the source of the infection is bacterial. Levels won't rise significantly with viral or noninfectious causes of inflammation surgery, trauma, burns.

Serum PCT is used as a biomarker to detect sepsis and severe sepsis caused by a bacterial organism. It should be drawn as soon as there's a suspected infection. Used in conjunction with other lab findings and clinical assessment, it can help confirm the diagnosis of sepsis, severe sepsis, or septic shock.

PCT levels can also guide antibiotic therapy. Decreasing PCT levels in a patient treated for a severe bacterial infection indicate a response to therapy.

PCT levels should be repeated every 24 to 48 hours to help determine effectiveness of treatment and patient prognosis. In response to a bacterial infection, PCT levels rise within 3 to 6 hours, peaking at 12 hours, with a half-life of 24 hours. PCT levels 1. Surviving sepsis campaign: However, the desire to minimize superinfections and other complications should not take precedence over giving an adequate course of therapy to cure the infection that caused the severe sepsis or septic shock.

We suggest the use of low procalcitonin levels or similar biomarkers to assist the clinician in the discontinuation of empiric antibiotics in patients who appeared septic, but have no subsequent evidence of infection grade 2C. This suggestion is predicated on the preponderance of the published literature relating to the use of procalcitonin as a tool to discontinue unnecessary antimicrobials [ 58 , 83 ]. However, clinical experience with this strategy is limited and the potential for harm remains a concern [ 83 ].

No evidence demonstrates that this practice reduces the prevalence of antimicrobial resistance or the risk of antibiotic-related diarrhea from C. One recent study failed to show any benefit of daily procalcitonin measurement in early antibiotic therapy or survival [ 84 ]. We suggest combination empiric therapy for neutropenic patients with severe sepsis grade 2B and for patients with difficult-to- treat, multidrug-resistant bacterial pathogens such as Acinetobacter and Pseudomonas spp.

For selected patients with severe infections associated with respiratory failure and septic shock, combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is suggested for P. Similarly, a more complex combination of beta-lactam and a macrolide is suggested for patients with septic shock from bacteremic Streptococcus pneumoniae infections grade 2B.

Complex combinations might be needed in settings where highly antibiotic-resistant pathogens are prevalent, with such regimens incorporating carbapenems, colistin, rifampin, or other agents. However, a recent controlled trial suggested that adding a fluoroquinolone to a carbapenem as empiric therapy did not improve outcome in a population at low risk for infection with resistant microorganisms [ 85 ].

De-escalation to the most appropriate single-agent therapy should be performed as soon as the susceptibility profile is known grade 2B. Exceptions would include aminoglycoside monotherapy, which should be generally avoided, particularly for P. A propensity-matched analysis, meta-analysis, and meta-regression analysis, along with additional observational studies, have demonstrated that combination therapy produces a superior clinical outcome in severely ill, septic patients with a high risk of death [ 86 , 87 , 88 , 89 , 90 ].

In light of the increasing frequency of resistance to antimicrobial agents in many parts of the world, broad-spectrum coverage generally requires the initial use of combinations of antimicrobial agents.

Combination therapy used in this context connotes at least two different classes of antibiotics usually a beta-lactam agent with a macrolide, fluoroquinolone, or aminoglycoside for select patients. A controlled trial suggested, however, that when using a carbapenem as empiric therapy in a population at low risk for infection with resistant microorganisms, the addition of a fluoroquinolone does not improve outcomes of patients [ 85 ].

A number of other recent observational studies and some small, prospective trials support initial combination therapy for selected patients with specific pathogens e. In some clinical scenarios, combination therapies are biologically plausible and are likely clinically useful even if evidence has not demonstrated improved clinical outcome [ 89 , 90 , 94 , 95 ].

Combination therapy for suspected or known Pseudomonas aeruginosa or other multiresistant Gram-negative pathogens, pending susceptibility results, increases the likelihood that at least 1 drug is effective against that strain and positively affects outcome [ 88 , 96 ].

Although patient factors may influence the length of antibiotic therapy, in general, a duration of 7—10 days in the absence of source control issues is adequate.

Thus, decisions to continue, narrow, or stop antimicrobial therapy must be made on the basis of clinician judgment and clinical information. Clinicians should be cognizant of blood cultures being negative in a significant percentage of cases of severe sepsis or septic shock, despite the fact that many of these cases are very likely caused by bacteria or fungi.

Clinicians should be cognizant that blood cultures will be negative in a significant percentage of cases of severe sepsis or septic shock, despite many of these cases are very likely caused by bacteria or fungi. We suggest that antiviral therapy be initiated as early as possible in patients with severe sepsis or septic shock of viral origin grade 2C.

Recommendations for antiviral treatment include the use of: Susceptibility to antivirals is highly variable in a rapidly evolving virus such as influenza, and therapeutic decisions must be guided by updated information regarding the most active, strain-specific, antiviral agents during influenza epidemics [ 99 , ].

The role of cytomegalovirus CMV and other herpesviruses as significant pathogens in septic patients, especially those not known to be severely immunocompromised, remains unclear. What is not known is whether CMV simply is a marker of disease severity or if the virus actually contributes to organ injury and death in septic patients [ ]. No treatment recommendations can be given based on the current level of evidence.

In those patients with severe primary or generalized varicella-zoster virus infections, and in rare patients with disseminated herpes simplex infections, antiviral agents such as acyclovir can be highly effective when initiated early in the course of infection [ ]. We recommend that antimicrobial agents not be used in patients with severe inflammatory states determined to be of noninfectious cause UG.

When infection is found not to be present, antimicrobial therapy should be stopped promptly to minimize the likelihood that the patient will become infected with an antimicrobial-resistant pathogen or will develop a drug-related adverse effect. Thus, the decisions to continue, narrow, or stop antimicrobial therapy must be made on the basis of clinician judgment and clinical information.

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We recommend that a specific anatomical diagnosis of infection requiring consideration for emergent source control e. We suggest that when infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and nonviable tissues has occurred grade 2B. The principles of source control in the management of sepsis include a rapid diagnosis of the specific site of infection and identification of a focus of infection amenable to source control measures specifically the drainage of an abscess, debridement of infected necrotic tissue, removal of a potentially infected device, and definitive control of a source of ongoing microbial contamination [ ].

Foci of infection readily amenable to source control measures include an intra-abdominal abscess or gastrointestinal perforation, cholangitis or pyelonephritis, intestinal ischemia or necrotizing soft tissue infection, and other deep space infection, such as an empyema or septic arthritis. Such infectious foci should be controlled as soon as possible following successful initial resuscitation [ , , ], and intravascular access devices that are potentially the source of severe sepsis or septic shock should be removed promptly after establishing other sites for vascular access [ , ].

An RCT comparing early to delayed surgical intervention for peripancreatic necrosis showed better outcomes with a delayed approach [ ]. Moreover, a randomized surgical study found that a minimally invasive, step-up approach was better tolerated by patients and had a lower mortality than open necrosectomy in necrotizing pancreatitis [ ], although areas of uncertainty exist, such as definitive documentation of infection and appropriate length of delay.

The selection of optimal source control methods must weigh the benefits and risks of the specific intervention as well as risks of transfer [ ]. Source control interventions may cause further complications, such as bleeding, fistulas, or inadvertent organ injury.

Surgical intervention should be considered when other interventional approaches are inadequate or when diagnostic uncertainty persists despite radiologic evaluation. We suggest that selective oral decontamination SOD and selective digestive decontamination SDD should be introduced and investigated as a method to reduce the incidence of VAP; this infection control measure can then be instituted in healthcare settings and regions where this methodology is found to be effective grade 2B.

Careful infection control practices e. The role of SDD with systemic antimicrobial prophylaxis and its variants e. However, the efficacy of SDD, its safety, propensity to prevent or promote antibiotic resistance, and cost-effectiveness remain debatable despite a number of favorable meta-analyses and controlled clinical trials [ ].

The data indicate an overall reduction in VAP but no consistent improvement in mortality, except in selected populations in some studies. Most studies do not specifically address the efficacy of SDD in patients who present with sepsis, but some do [ , , ]. Oral CHG is relatively easy to administer, decreases risk of nosocomial infection, and reduces the potential concern over promotion of antimicrobial resistance by SDD regimens.

This remains a subject of considerable debate, despite the recent evidence that the incidence of antimicrobial resistance does not change appreciably with current SDD regimens [ , , ]. We recommend crystalloids be used as the initial fluid of choice in the resuscitation of severe sepsis and septic shock grade 1B. We recommend against the use of hydroxyethyl starches HES for fluid resuscitation of severe sepsis and septic shock grade 1B. We suggest the use of albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids grade 2C.

Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock grade 1B. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock grade 1B.

Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids grade 2C. More rapid administration and greater amounts of fluid may be needed in some patients grade 1C. Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic e. Epinephrine added to and potentially substituted for norepinephrine when an additional agent is needed to maintain adequate blood pressure grade 2B.

Vasopressin 0. Low dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension and vasopressin doses higher than 0.

Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia grade 2C.

All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available UG. Not using a strategy to increase cardiac index to predetermined supranormal levels grade 1B. Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability see goals for Initial Resuscitation.

In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of mg per day grade 2C. Not using the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone grade 2B. In treated patients hydrocortisone tapered when vasopressors are no longer required grade 2D. Corticosteroids not be administered for the treatment of sepsis in the absence of shock grade 1D.

The absence of any clear benefit following the administration of colloid solutions compared to crystalloid solutions, together with the expense associated with colloid solutions, supports a high-grade recommendation for the use of crystalloid solutions in the initial resuscitation of patients with severe sepsis and septic shock. A meta-analysis of 56 randomized trials found no overall difference in mortality between crystalloids and artificial colloids modified gelatins, HES, dextran when used for initial fluid resuscitation [ ].

However, these solutions increased substantially the risk of acute kidney injury RR, 1. The evidence of harm observed in the 6S and CHEST studies and the meta-analysis supports a high-level recommendation advising against the use of HES solutions in patients with severe sepsis and septic shock, particularly since other options for fluid resuscitation exist.

The CRYSTAL trial, another large prospective clinical trial comparing crystalloids and colloids, was recently completed and will provide additional insight into HES fluid resuscitation. The SAFE study indicated that albumin administration was safe and equally as effective as 0. These data support a low-level recommendation regarding the use of albumin in patients with sepsis and septic shock personal communication from J.

More rapid administration and greater amounts of fluid may be needed in some patients see Initial Resuscitation recommendations grade 1C.

We recommend that a fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic e. These tests are based on monitoring changes in stroke volume during mechanical ventilation or after passive leg raising in spontaneously breathing patients. The diagnostic OR of fluid responsiveness was Utility of pulse pressure variation and stroke volume variation is limited in the presence of atrial fibrillation, spontaneous breathing, and low pressure support breathing.

These techniques generally require sedation. Vasopressor therapy is required to sustain life and maintain perfusion in the face of life-threatening hypotension, even when hypovolemia has not yet been resolved. Below a threshold MAP, autoregulation in critical vascular beds can be lost, and perfusion can become linearly dependent on pressure. Thus, some patients may require vasopressor therapy to achieve a minimal perfusion pressure and maintain adequate flow [ , ].

Supplementing endpoints, such as blood pressure, with assessment of regional and global perfusion, such as blood lactate concentrations, skin perfusion, mental status, and urine output, is important. Adequate fluid resuscitation is a fundamental aspect of the hemodynamic management of patients with septic shock and should ideally be achieved before vasopressors and inotropes are used; however, using vasopressors early as an emergency measure in patients with severe shock is frequently necessary, as when diastolic blood pressure is too low.

When that occurs, great effort should be directed to weaning vasopressors with continuing fluid resuscitation. We suggest epinephrine added to and potentially substituted for norepinephrine when an additional agent is needed to maintain adequate blood pressure grade 2B.

Vasopressin up to 0. Low-dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension, and vasopressin doses higher than 0.

We have decided not to lower the evidence quality. Although some human and animal studies suggest epinephrine has deleterious effects on splanchnic circulation and produces hyperlactatemia, no clinical evidence shows that epinephrine results in worse outcomes, and it should be the first alternative to norepinephrine.

Vasopressin levels in septic shock have been reported to be lower than anticipated for a shock state [ ]. Low doses of vasopressin may be effective in raising blood pressure in patients, refractory to other vasopressors and may have other potential physiologic benefits [ , , , , , ].

Terlipressin has similar effects but is long acting [ ]. This has been called relative vasopressin deficiency because in the presence of hypotension, vasopressin would be expected to be elevated.

The significance of this finding is unknown. The VASST trial, a randomized, controlled trial comparing norepinephrine alone to norepinephrine plus vasopressin at 0. Higher doses of vasopressin have been associated with cardiac, digital, and splanchnic ischemia and should be reserved for situations where alternative vasopressors have failed [ ]. Indeed, the relative risk of dying was 1.

However, the risk of supraventricular arrhythmias was increased with norepinephrine RR, 7. Cardiac output measurement targeting maintenance of a normal or elevated flow is desirable when these pure vasopressors are instituted.

A large randomized trial and meta-analysis comparing low-dose dopamine to placebo found no difference in either primary outcomes peak serum creatinine, need for renal replacement, urine output, time to recovery of normal renal function or secondary outcomes survival to either ICU or hospital discharge, ICU stay, hospital stay, arrhythmias [ , ]. Thus, the available data do not support administration of low doses of dopamine solely to maintain renal function.

We recommend that all patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available UG. In shock states, estimation of blood pressure using a cuff is commonly inaccurate; use of an arterial cannula provides a more appropriate and reproducible measurement of arterial pressure. These catheters also allow continuous analysis so that decisions regarding therapy can be based on immediate and reproducible blood pressure information.

We recommend against the use of a strategy to increase cardiac index to predetermined supranormal levels grade 1B. Dobutamine is the first choice inotrope for patients with measured or suspected low cardiac output in the presence of adequate left ventricular filling pressure or clinical assessment of adequate fluid resuscitation and adequate MAP. Septic patients who remain hypotensive after fluid resuscitation may have low, normal, or increased cardiac outputs.

When the capability exists for monitoring cardiac output in addition to blood pressure, a vasopressor, such as norepinephrine, may be used separately to target specific levels of MAP and cardiac output. Large prospective clinical trials, which included critically ill ICU patients who had severe sepsis, failed to demonstrate benefit from increasing oxygen delivery to supranormal targets by use of dobutamine [ , ].

If evidence of tissue hypoperfusion persists despite adequate intravascular volume and adequate MAP, a viable alternative other than reversing underlying insult is to add inotropic therapy. We suggest not using intravenous hydrocortisone as a treatment of adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability see goals for Initial Resuscitation. The response of septic shock patients to fluid and vasopressor therapy seems to be an important factor in selection of patients for optional hydrocortisone therapy.

Two smaller RCTs also showed significant effects on shock reversal with steroid therapy [ , ]. In contrast, a large, European multicenter trial CORTICUS that enrolled patients without sustained shock and had a lower risk of death than the French trial failed to show a mortality benefit with steroid therapy [ ].

The use of the ACTH test responders and nonresponders did not predict the faster resolution of shock. In recent years, several systematic reviews have examined the use of low-dose hydrocortisone in septic shock with contradictory results: Annane et al. In parallel, Sligl and colleagues [ ] used a similar technique, but only identified eight studies for their meta-analysis, six of which had a high-level RCT design with low risk of bias [ ].

In contrast to the aforementioned review, this analysis revealed no statistically significant difference in mortality RR, 1. Both reviews, however, confirmed the improved shock reversal by using low-dose hydrocortisone [ , ]. A recent review on the use of steroids in adult septic shock underlined the importance of selection of studies for systematic analysis [ ] and identified only 6 high-level RCTs as adequate for systematic review [ , , , , , ].

We suggest not using the ACTH stimulation test to identify the subset of adults with septic shock who should receive hydrocortisone grade 2B. In one study, the observation of a potential interaction between steroid use and ACTH test was not statistically significant [ ]. Furthermore, no evidence of this distinction was observed between responders and nonresponders in a recent multicenter trial [ ]. Random cortisol levels may still be useful for absolute adrenal insufficiency; however, for septic shock patients who suffer from relative adrenal insufficiency no adequate stress response , random cortisol levels have not been demonstrated to be useful.

Cortisol immunoassays may over- or underestimate the actual cortisol level, affecting the assignment of patients to responders or nonresponders [ ]. Although the clinical significance is not clear, it is now recognized that etomidate, when used for induction for intubation, will suppress the hypothalamic—pituitary—adrenal axis [ , ]. Moreover, a subanalysis of the CORTICUS trial [ ] revealed that the use of etomidate before application of low-dose steroids was associated with an increased day mortality rate [ ].

We suggest that clinicians taper the treated patient from steroid therapy when vasopressors are no longer required grade 2D. There has been no comparative study between a fixed-duration and clinically guided regimen or between tapering and abrupt cessation of steroids. Three RCTs used a fixed-duration protocol for treatment [ , , ], and therapy was decreased after shock resolution in two RCTs [ , ].

In four studies, steroids were tapered over several days [ , , , ], and steroids were withdrawn abruptly in two RCTs [ , ]. One crossover study showed hemodynamic and immunologic rebound effects after abrupt cessation of corticosteroids [ ].

What's new in sepsis?

We recommend that corticosteroids not be administered for the treatment of sepsis in the absence of shock grade 1D. Steroids may be indicated in the presence of a history of steroid therapy or adrenal dysfunction, but whether low-dose steroids have a preventive potency in reducing the incidence of severe sepsis and septic shock in critically ill patients cannot be answered.

A preliminary study of stress-dose level steroids in community-acquired pneumonia showed improved outcome measures in a small population [ ], and a recent confirmatory RCT revealed reduced hospital length of stay without affecting mortality [ ]. When low-dose hydrocortisone is given, we suggest using continuous infusion rather than repetitive bolus injections grade 2D.

Several randomized trials on the use of low-dose hydrocortisone in septic shock patients revealed a significant increase of hyperglycemia and hypernatremia [ ] as side effects. A small prospective study demonstrated that repetitive bolus application of hydrocortisone leads to a significant increase in blood glucose; this peak effect was not detectable during continuous infusion.

Furthermore, considerable inter-individual variability was seen in this blood glucose peak after the hydrocortisone bolus [ ]. Not using erythropoietin as a specific treatment of anemia associated with severe sepsis grade 1B. Fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures grade 2D. Not using antithrombin for the treatment of severe sepsis and septic shock grade 1B. Not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock grade 2B.

Recruitment maneuvers be used in sepsis patients with severe refractory hypoxemia grade 2C. That mechanically ventilated sepsis patients be maintained with the head of the bed elevated to 30—45 degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia grade 1B. That noninvasive mask ventilation NIV be used in that minority of sepsis-induced ARDS patients in whom the benefits of NIV have been carefully considered and are thought to outweigh the risks grade 2B.

That a weaning protocol be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria: If the spontaneous breathing trial is successful, consideration should be given for extubation grade 1A.

Against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS grade 1A. A conservative rather than liberal fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion grade 1C.

In the absence of specific indications such as bronchospasm, not using beta 2-agonists for treatment of sepsis- induced ARDS. Grade 1B. Continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration endpoints grade 1B. Neuromuscular blocking agents NMBAs be avoided if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation.

If NMBAs must be maintained, either intermittent bolus as required or continuous infusion with train-of-four monitoring of the depth of blockade should be used grade 1C.

When the risk decreases start pharmacoprophylaxis grade 2C. When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA grade 2D. Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding e. Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating supplementation in patients with severe sepsis grade 2C. Address goals of care as early as feasible, but no later than within 72 hours of ICU admission grade 2C.

No significant differences in day mortality rates were observed between treatment groups in the subgroup of patients with severe infections and septic shock Red blood cell transfusion in septic patients increases oxygen delivery but does not usually increase oxygen consumption [ , , ]. We recommend not using erythropoietin as a specific treatment of anemia associated with severe sepsis grade 1B. No specific information regarding erythropoietin use in septic patients is available, but clinical trials of erythropoietin administration in critically ill patients show some decrease in red cell transfusion requirement with no effect on clinical outcome [ , ].

The effect of erythropoietin in severe sepsis and septic shock would not be expected to be more beneficial than in other critical conditions. Patients with severe sepsis and septic shock may have coexisting conditions that meet indications for the use of erythropoietin. We suggest that fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures grade 2D.

Although clinical studies have not assessed the impact of transfusion of fresh frozen plasma on outcomes in critically ill patients, professional organizations have recommended it for coagulopathy when there is a documented deficiency of coagulation factors increased prothrombin time, international normalized ratio, or partial thromboplastin time and the presence of active bleeding or before surgical or invasive procedures [ , , , ].

In addition, transfusion of fresh frozen plasma usually fails to correct the prothrombin time in nonbleeding patients with mild abnormalities [ , ]. No studies suggest that correction of more severe coagulation abnormalities benefits patients who are not bleeding.

We recommend against antithrombin administration for the treatment of severe sepsis and septic shock grade 1B. A phase III clinical trial of high-dose antithrombin did not demonstrate any beneficial effect on day all-cause mortality in adults with severe sepsis and septic shock. High-dose antithrombin was associated with an increased risk of bleeding when administered with heparin [ ]. Although a post hoc subgroup analysis of patients with severe sepsis and high risk of death showed better survival in patients receiving antithrombin, this agent cannot be recommended until further clinical trials are performed [ ].

Guidelines for transfusion of platelets are derived from consensus opinion and experience in patients with chemotherapy-induced thrombocytopenia. Patients with severe sepsis are likely to have some limitation of platelet production similar to that in chemotherapy-treated patients, but they also are likely to have increased platelet consumption.

Recommendations take into account the etiology of thrombocytopenia, platelet dysfunction, risk of bleeding, and presence of concomitant disorders [ , , , , ]. Factors that may increase the bleeding risk and indicate the need for a higher platelet count are frequently present in patients with severe sepsis. Sepsis itself is considered to be a risk factor for bleeding in patients with chemotherapy-induced thrombocytopenia. We suggest not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock grade 2B.

These findings are in accordance with those of 2 older meta-analyses [ , ] from other Cochrane authors. One systematic review [ ] included a total of 21 trials and showed a relative risk of death of 0. Similarly, Laupland et al. When only high-quality studies were pooled, the OR for mortality was 0. Two meta-analyses, which used less strict criteria to identify sources of bias or did not state their criteria for the assessment of study quality, found significant improvement in patient mortality with IVIG treatment [ , ].

In contrast to the most recent Cochrane review, Kreymann et al. Subgroup effects between IgM-enriched and nonenriched formulations reveal substantial heterogeneity. In addition, indirectness and publication bias were considered in grading this recommendation. The low-quality evidence led to the grading as a weak recommendation. The statistical information that comes from the high-quality trials does not support a beneficial effect of polyclonal IVIG.

We encourage conducting large multicenter studies to further evaluate the effectiveness of other polyclonal immunoglobulin preparations given intravenously in patients with severe sepsis. Selenium was administered in the hope that it could correct the known reduction of selenium concentration in sepsis patients and provide a pharmacologic effect through an antioxidant defense.

Although some randomized controlled trials are available, the evidence on the use of intravenous selenium is still very weak. Only one large clinical trial has examined the effect on mortality rates, and no significant impact was reported on the intent-to-treat population with severe systemic inflammatory response syndrome, sepsis, or septic shock OR, 0.

Overall, there was a trend toward a concentration-dependent reduction in mortality; no differences in secondary outcomes or adverse events were detected. A French RCT in a small population revealed no effect on primary shock reversal or secondary days on mechanical ventilation, ICU mortality endpoints [ ].

This is in accordance with 2 RCTs that resulted in reduced number of infectious episodes [ ] or increase in glutathione peroxidase concentrations [ ]; neither study, however, showed a beneficial effect on secondary outcome measures renal replacement, ICU mortality [ , ]. A more recent large RCT tried to determine if the addition of relatively low doses of supplemental selenium glutamine was also tested in a two-factorial design to parenteral nutrition in critically ill patients reduces infections and improves outcome [ ].

Selenium supplementation did not significantly affect the development of a new infection OR, 0. In addition, length of stay, days of antibiotic use, and modified Sequential Organ Failure Assessment score were not significantly affected by selenium [ ]. In addition to the lack of evidence, the questions of optimal dosing and application mode remain unanswered.

Reported high-dose regimens have involved a loading dose followed by an infusion, while animal trials suggest that bolus dosing could be more effective [ ]; this, however, has not been tested in humans. These unsolved problems require additional trials, and we encourage conducting large multicenter studies to further evaluate the effectiveness of intravenous selenium in patients with severe sepsis.

This recommendation does not exclude the use of low-dose selenium as part of the standard minerals and oligo-elements used during total parenteral nutrition TPN. The SSC guidelines recommended use of rhAPC in line with the product labeling instructions required by the US and European regulatory authorities with a grade B quality of evidence [ 7 , 8 ]. By the time of publication of the SSC guidelines, additional studies of rhAPC in severe sepsis as required by regulatory agencies had shown it ineffective in less severely ill patients with severe sepsis as well as in children [ , ].

The drug was withdrawn from the market and is no longer available, negating any need for an SSC recommendation regarding its use. Several multicenter randomized trials have been performed in patients with established ARDS to evaluate the effects of limiting inspiratory pressure through moderation of tidal volume [ , , , , ]. These studies showed differing results that may have been caused by differences in airway pressures in the treatment and control groups [ , , ].

Several meta-analyses suggest decreased mortality in patients with a pressure- and volume-limited strategy for established ARDS [ , ]. Patients with profound metabolic acidosis, high obligate minute ventilations, or short stature may require additional manipulation of tidal volumes. High tidal volumes that are coupled with high plateau pressures should be avoided in ARDS. Using volume- and pressure-limited ventilation may lead to hypercapnia with maximum tolerated set respiratory rates.

In such cases, hypercapnia that is otherwise not contraindicated e. Sodium bicarbonate or tromethamine THAM infusion may be considered in selected patients to facilitate use of limited ventilator conditions that result in permissive hypercapnia [ , ].

A number of observational trials in mechanically ventilated patients have demonstrated a decreased risk of developing ARDS when smaller trial volumes are used [ , , , ]. Accordingly, high tidal volumes and plateau pressures should be avoided in mechanically ventilated patients at risk for developing ARDS, including those with sepsis.

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No single mode of ventilation pressure control, volume control has consistently been shown to be advantageous when compared with any other that respects the same principles of lung protection. We recommend that PEEP be applied to avoid alveolar collapse at end expiration atelectotrauma grade 1B. This will increase Pa o 2 when PEEP is applied through either an endotracheal tube or a face mask [ , , ].

Three large multicenter trials using higher versus lower levels of PEEP in conjunction with low tidal volumes did not uncover benefit or harm [ , , ]. Two options are recommended for PEEP titration. One option is to titrate PEEP and tidal volume according to bedside measurements of thoracopulmonary compliance with the objective of obtaining the best compliance, reflecting a favorable balance of lung recruitment and overdistension [ ]. The second option is to titrate PEEP based on severity of oxygenation deficit and guided by the F i o 2 required to maintain adequate oxygenation [ , , ].

The application of transient sustained use of continuous positive airway pressure CPAP appears to improve oxygenation in patients initially, but these effects can be transient [ ]. Although selected patients with severe hypoxemia may benefit from recruitment maneuvers in conjunction with higher levels of PEEP, little evidence supports the routine use in all ARDS patients [ ].

Blood pressure and oxygenation should be monitored and recruitment maneuvers discontinued if deterioration in these variables is observed.

Several small studies and one large study in patients with hypoxemic respiratory failure or ARDS have shown that most patients respond to the prone position with improved oxygenation [ , , , ]. None of the individual trials of prone positioning in patients with ARDS or hypoxemic respiratory failure demonstrated a mortality benefit [ , , , ].

Prone positioning may be associated with potentially life-threatening complications, including accidental dislodging of the endotracheal and chest tubes; these complications occur more frequently in patients in the prone compared with supine position [ ]. Other methods to treat refractory hypoxemia, including high-frequency oscillatory ventilation, airway pressure release ventilation, and extracorporeal membrane oxygenation [ ], may be considered as rescue therapies in centers with expertise and experience with their use [ , , , , ].

Inhaled nitric oxide does not improve mortality rates in patients with ARDS and should not be routinely used [ ]. We recommend that mechanically ventilated sepsis patients be maintained with the head of the bed elevated between 30 and 45 degrees to limit aspiration risk and to prevent the development of VAP grade 1B.

The semi-recumbent position has been demonstrated to decrease the incidence of VAP [ ]. However, the bed position was monitored only once a day, and patients who did not achieve the desired bed elevation were not included in the analysis [ ]. One study did not show a difference in incidence of VAP between patients maintained in supine and semi-recumbent positions [ ]; patients assigned to the semi-recumbent group did not consistently achieve the desired head of the bed elevation, and the head of bed elevation in the supine group approached that of the semi-recumbent group by day 7 [ ].

When necessary, patients may be laid flat for procedures, hemodynamic measurements, and during episodes of hypotension. Patients should not be fed enterally while supine. We suggest that noninvasive mask ventilation NIV be used in that minority of sepsis-induced ARDS patients in whom the benefits of NIV have been carefully considered and are thought to outweigh the risks grade 2B.

Obviating the need for airway intubation confers multiple advantages: Two RCTs in patients with acute respiratory failure demonstrated improved outcome with the use of NIV when it can be used successfully [ , ]. Unfortunately, only a small percentage of sepsis patients with life-threatening hypoxemia can be managed in this way [ , ].

NIV should be considered in patients with sepsis-induced ARDS if they are responsive to relatively low levels of pressure support and PEEP with stable hemodynamics, can be made comfortable, and are easily arousable; if they are able to protect the airway and spontaneously clear the airway of secretions; and if they are anticipated to recover rapidly from the precipitating insult [ , ]. A low threshold for airway intubation should be maintained.

We recommend that a weaning protocol be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria: If the spontaneous breathing trial is successful, extubation should be considered grade 1A. Studies demonstrated that daily spontaneous breathing trials in appropriately selected patients reduce the duration of mechanical ventilation [ , ].

These breathing trials should be conducted in conjunction with a spontaneous awakening trial [ ]. Successful completion of spontaneous breathing trials leads to a high likelihood of successful early discontinuation of mechanical ventilation.

We recommend against the routine use of the pulmonary artery catheter for patients with sepsis-induced ARDS grade 1A. In addition, other studies in different types of critically ill patients have failed to show definitive benefit with routine use of the PA catheter [ , , ]. Well-selected patients remain appropriate candidates for PA catheter insertion only when the answers to important management decisions depend on information solely obtainable from direct measurements made within the PA [ , ].

We recommend a conservative fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion grade 1C. Mechanisms for the development of pulmonary edema in patients with ARDS include increased capillary permeability, increased hydrostatic pressure, and decreased oncotic pressure [ ].

Small prospective studies in patients with critical illness and ARDS have suggested that low weight gain is associated with improved oxygenation [ ] and fewer days of mechanical ventilation [ , ].

This strategy was only used in patients with established ARDS, some of whom had shock present during the ICU stay, and active attempts to reduce fluid volume were conducted only outside periods of shock.

Patients with sepsis-induced ARDS often develop increased vascular permeability. In one, a comparison of aerosolized albuterol and placebo in patients with ARDS, the trial was stopped for futility [ ]. Patients receiving albuterol had higher heart rates on day 2, and a trend was detected toward decreased ventilator-free days days alive and off the ventilator. The rates of death before discharge were More than half of the patients enrolled in this trial had pulmonary or nonpulmonary sepsis as the cause of the ARDS [ ].

Patients treated with salbutamol had increased day mortality rates 34 vs. We recommend that either continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration endpoints grade 1B. A growing body of evidence indicates that limiting the use of sedation in critically ill ventilated patients can reduce the duration of mechanical ventilation and ICU and hospital lengths of stay [ , , ].

While studies limiting sedation have been performed in a wide range of critically ill patients, there is little reason to assume that septic patients will not derive benefit from this approach [ ]. The use of protocols for sedation is one method to limit sedation use, and a randomized, controlled clinical trial found that protocolized sedation compared with usual care reduced duration of mechanical ventilation, lengths of stay, and tracheostomy rates [ ].

Avoidance of sedation is another strategy. A recent observational study of critically ill patients suggests that deep sedation is common in mechanically ventilated patients [ ]. A randomized, controlled clinical trial found that patients treated with intravenous morphine boluses preferentially, had significantly more days without ventilation, shorter stay in ICU and hospital, than patients who received sedation propofol and midazolam in addition to morphine [ ].

However, agitated delirium was more frequently detected in the intervention group. Although not specifically studied in patients with sepsis, the administration of intermittent sedation, daily sedative interruption, and systematic titration to a predefined endpoint have been demonstrated to decrease the duration of mechanical ventilation [ , , , ].

Patients receiving neuromuscular blocking agents NMBAs must be individually assessed regarding discontinuation of sedative drugs because the neuromuscular blockade must first be reversed. The use of intermittent vs. Clinical trials have evaluated daily interruption of continuous sedative infusions. A prospective, randomized controlled trial in mechanically ventilated adults receiving continuous intravenous sedation demonstrated that a daily interruption in the continuous sedative infusion until the patient was awake decreased the duration of mechanical ventilation and ICU length of stay [ ].

Although the patients did receive continuous sedative infusions in this study, the daily interruption and awakening allowed for titration of sedation, in effect making the dosing intermittent. In addition, a paired spontaneous awakening trial combined with a spontaneous breathing trial decreased the duration of mechanical ventilation, length of ICU and hospital stay, and 1-year mortality [ ].

More recently, a multicenter randomized trial compared protocolized sedation with protocolized sedation plus daily sedation interruption in critically ill mechanically ventilated medical and surgical patients [ ]. There were no differences in duration of mechanical ventilation or lengths of stay between the groups; and daily interruption was associated with higher daily opioid and benzodiazepines doses, as well as higher nurse workload.

Additionally, a randomized prospective blinded observational study demonstrated that although myocardial ischemia is common in critically ill ventilated patients, daily sedative interruption is not associated with an increased occurrence of myocardial ischemia [ ].

Regardless of sedation approach, early physical rehabilitation should be a goal [ ]. We recommend that NMBAs be avoided if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation.

No evidence exists that neuromuscular blockade in this patient population reduces mortality or major morbidity. In addition, no studies have been published that specifically address the use of NMBAs in septic patients. When appropriately used, these agents may improve chest wall compliance, prevent respiratory dyssynchrony, and reduce peak airway pressures [ ].

Muscle paralysis may also reduce oxygen consumption by decreasing the work of breathing and respiratory muscle blood flow [ ]. However, a randomized, placebo-controlled clinical trial in patients with severe sepsis demonstrated that oxygen delivery, oxygen consumption, and gastric intramucosal pH were not improved during deep neuromuscular blockade [ ]. The investigators used a high fixed dose of cisatracurium without train-of-four monitoring, and half of the patients in the placebo group received at least a single dose of NMBA.

Whether another NMBA would have similar effects is unknown. Although many of the patients enrolled into this trial appeared to meet sepsis criteria, it is not clear whether similar results would occur in sepsis patients. An association between NMBA use and myopathies and neuropathies has been suggested by case studies and prospective observational studies in the critical care population [ , , , , ], but the mechanisms by which NMBAs produce or contribute to myopathies and neuropathies in these patients are unknown.

Although no studies are specific to the septic patient population, it seems clinically prudent, based on existing knowledge, that NMBAs not be administered unless there is a clear indication for neuromuscular blockade that cannot be safely achieved with appropriate sedation and analgesia [ ].

Only one prospective RCT has compared peripheral nerve stimulation and standard clinical assessment in ICU patients [ ]. Rudis et al. The peripheral nerve stimulation group received less drug and recovered neuromuscular function and spontaneous ventilation faster than the control group. Nonrandomized observational studies have suggested that peripheral nerve monitoring reduces or has no effect on clinical recovery from NMBAs in the ICU [ , ].

Benefits to neuromuscular monitoring, including faster recovery of neuromuscular function and shorter intubation times, appear to exist. A potential for cost savings reduced total dose of NMBAs and shorter intubation times also may exist, although this has not been studied formally.